The present invention relates to a novel single nucleotide polymorphism (SNP) in p21waf1/cip1 cyclin dependent kinase inhibitor gene and its association with cancer. More specifically, p21waf1/cip1, an important regulator of the cell cycle, binds to PCNA and acts as a mediator of growth suppressing and apoptosis promoting functions of p53.
The citations noted in this application form a part of this disclosure, and are incorporated herein by reference.
Initiation, progression and completion of the cell cycle are regulated by various cyclins and cyclin-dependent kinases (CDKs), which are critical for cell growth. Genetic alteration and deregulation of CDKs and their regulators is closely associated with abnormal proliferation. Tumour development is intricately linked to increased cell proliferation or decreased apoptosis (programmed cell death). The human p21waf1/cip1 localized to the chromosome 6p21.2 encodes a cyclin dependent kinase inhibitor, unregulated by wild type tumor suppressor protein p53, whose cellular level is elevated by genotoxic stress leading to either cell cycle arrest or cell death (Gujuluva et al., 1994; El-Deiry et al., 1995). Alterations in p21waf1/cip1 may adversely affect the regulation of cellular proliferation and increase the susceptibility to cancer. p21waf1/cip1 polymorphisms have been observed in various human cancers. The polymorphic variants have been reported to occur more frequently in cancer patients than in healthy individuals suggesting a role in increased susceptibility for the development of some types of cancers Mousses et al., 1995; Facher et al., 1997).
Although some polymorphisms have been identified in the p21waf1/cip1 gene, there is a continuing need in the art to search for novel, hitherto unobserved, alterations, which may be useful in predicting susceptibility to cancer and can lead to new diagnostic and therapeutic tools. The goal of this study was to analyze the alterations in p21waf1/cip1 gene and its expression in relation to p53 status in esophageal squamous cell carcinoma, and determine their relevance in predicting predisposition to cancer and potential as a molecular diagnostic marker.
The main object of the invention is to provide a method for screening subjects having risk or at risk of having oesophageal cancer by analysis of a p21waf1/cip1 gene polymorphism.
Another object of the invention is to provide a useful target for linkage analysis and disease association studies.
Yet another object of the invention is to provide a method for identifying the wild type and codon 149 polymorphic variant.
Another object of the invention is to provide a method to analyze the alteration in p21waf1/cip1 gene and its expression in relation to p53 status in esophageal carcinoma.
Yet another object is to study the relationship of p53 status in esophageal carcinoma and determine its relevance in predicting pre-disposition to cancer.
Yet another object is to develop a novel molecular diagnostic marker useful in the detection of esophageal carcinoma.
Still another embodiment of the invention is to screen for novel drugs that target the variant gene product.
The present invention relates to analysis of the alterations in p21waf1/cip1 gene and its expression in relation to p53 status in oesophageal cancer, a method for screening of subjects having or at risk of having esophageal cancer by detection of the polymorphism in p21waf1/cip1 gene, and use thereof as a diagnostic marker.